Project Summary/Abstract Upon pathogen infection, cellular stress pathways and microbial killing pathways are rapidly activated by the host immune system. These pathways must be tightly regulated as insufficient or excessive immune responses have deleterious consequences. Recent studies indicate that the nervous system plays a critical role in the regulation of immune responses. However, the precise mechanisms behind this regulation remain unclear. While many aspects of neural control of immunity are difficult to dissect in complex mammalian systems or in vitro, the nematode Caenorhabditis elegans has proven to be an excellent model organism for studying such control due to its simple, well-defined nervous system and accessibility to genetic, genomic, and molecular analyses. Our recent studies demonstrated that OCTR-1, a putative G protein-coupled receptor for catecholamines, functions in two sensory neurons ASH and ASI to suppress innate immunity by inhibiting immune signaling pathways. These findings highlight the importance of specific genes and neurons in the regulation of immunity. Two important questions, however, remain unanswered. First, what is the ligand that activates OCTR-1 in the sensory neurons? Second, which neurons form circuits with ASH and ASI to control the innate immune responses? In the current proposal, we seek to answer both questions. We will use a variety of molecular and genetic approaches to identify OCTR-1 ligand(s) and assess the roles of candidate neurons in the OCTR-1 neural circuit. The proposed studies will uncover molecules and cells involved in the activation and mediation of the OCTR-1-dependent neural signaling, which will give us a better understanding of how the nervous system controls innate immunity. Dysregulation of innate immunity to pathogens has been linked to a number of pathological states in human, such as chronic inflammatory diseases and autoimmune diseases. Information gleaned from the proposed studies will be useful to the development of more effective treatments for innate immune disorders.